7alpha-acylthio substitution products of 4-androsten-3-ones



United States PatentOfiice "Ia- AC YLTHIO sUBsTrrUTIoN PRODUCTS F 4-ANDROSTEN-3-0NES Raymond M. Dodson, Park Ridge, and Robert C. Tweit, Wilmette, 111., assignors to G. D. Searle & Co., Chicago,

11]., a corporation of Delaware No Drawing. Application December 31, 1957 Serial No.706,261

5 Claims. (Cl. 260-3975) The present invention relates to 7macylthio'substitution products of 4-androsten-3-ones. The compositions of this invention can be represented by the general structural formula -acyl wherein R" represents hydrogen or a lower alkyl radical, to a 4,6-androstadien-3-one which has the structural formula wherein Z has the same meaning as aforesaid. The addition reaction proceeds fairly rapidly at elevated temperatures, such as those in excess of 50, and can be carried out optionally under the influence of ultraviolet light. In carrying out the addition reaction with lower boiling thioalkanoic acids, such as thioacetic acid, it is convenient to conduct the reaction at the reflux temperature of the reaction mixture; whereas with higher boiling thioalkanoic acids it is convenient to conduct the reaction at a temperature of about 90-100". Heating periods of up to a few hours are sufiicient to achieve substantial conversion to the desired reaction product. Typically, the desired compound is obtained in a satisfactory state of purity by direct filtration of the cooled reaction mixture, preceded, where necessary, by removal of excess thioalkanoic acid.

ethyl acetate and benzene. I

The free mercaptan corresponding to the 7-acylthio derivatives of the present invention can be obtained by the mild hydrolysis of the acylthio derivatives.

The addition of the thioalltanoic'acids to the 6,7-double bond of the starting materials employed in the practice.

of this invention proceeds under steric influences such that of the stereoisomers formed, one is obtained in predominant amount. The isomer obtained in predominant amount has in each case been characterized herein'as possessing the zit-configuration of the 7-acylthio" group.

This configuration has been designated in order to provide a more complete expositionof the present invention, and

in order that the specification shall constitute a more However, the designated useful contribution to the art. configuration of the 'l -acylthio group is based upon an analysis of molecular rotation data presently appearing in the chemical literature, and is therefore'not to be interpreted except in relation to the state of the'art presently This invention will appear more fully from'the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention'is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and in methods will beapparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centi grade C.) and quantities of materials are expressed in parts by weight and parts by volume which bear the same relation one to the other as kilograms to liters.

Example 1 A solution of 2 parts by weight of 4,6-androstadiene- 3,17-dione and 1 part by volume of thioacetic acid is heated and irradiated with ultraviolet light for 2 hours. The reaction mixture is evaporated to dryness under vacuum to yield 7-acetylthio-4-androstene-3,l7-dione as an amorphous solid; [a] =-l-87.5; ultraviolet extinction coeflicient 16,300 at 238 millimicrons.

Example 2 t A mixture of 1.5 parts by weight of 17p-hydroxy-4,6- androstadien-3-one benzoate and 1.5 parts by volume of thioacetic acid is heated on the steam bath for 1 hour.

A further quantity of 1 part by volume of thioaceticacid is added and the heating continued for 2 hours. After standing overnight, the mixture is heated for l hour, the reaction mixture concentrated to dryness under vacuum and the residue triturated with 20 parts by volume of ether. Part of the solid crystallizes and the crystals and the supernatant liquorrare decanted and the glass remaining dissolved in 10 parts by volume of methylene chloride. The methylene chloride solution is concentrated to dryness. and triturated with 20 parts by volume of ether. The precipitate which forms is recrystallized from acetone-ether to yield 7e-acetylthiotestosterone benzoate; melting point 185-186"; [oz] =+37.

Example 3 A mixture of 8 parts by weight of 17p-hydroxy-4,6- andros'tadien-3-one and 8 parts by volume of thiopropionic acid is heated on the steam bath for 30 minutes, cooled, diluted with parts by volume of ether and the solid residue which forms collected and recrystallized from acetone-ether to .yield 7u-propionylthiotestosterone;

Patented Nov. 4, 1958 melting point 234-236" (dec.)-; ultraviolet extinction coefiicient 19,800 at 238 millimicrons.

. I Example 4 -A1rnixture ot 1 partiby yeightgof 7a -propionylthiotestosterone; 4.- parts by volume of isobutyric V anhydn'de 8 par ts by volume of pyridine are warmed; gently unti k the solid is: dissolved and then allowed to,stand overnight; at room temperature. The mixture is: poured into water, extracted with methylene chloride, the methylerre -chloride extract washed successively with sodium car onate; solutiontand: w t r, an fin lly concentrated to dryness in vacuo. The residue is dissolved; in- 100 Parts-by vo ume benzene. and. he. r sill ingr ton.

Ex a mPIe Jv A mi t r o parts y i ht o fi-hydr xyfladrostadien-3-one propionate and 1 'part by;;volurne of hiqpr pion c ac d ea ed; 1,- e: team ba h: for; 4 hou sin vacuo, the residue dissolved'in l QQparts by volume of; benzene; and, the resulting solgtion chromatographed; on

silicag el; The chromatographic column is washed with 2000 parts by-volumeof benzene'andelutedith 20,00-

parts by volume of 5% ethyl acetate-in benzene. The solvent is removed from the eluate; to yield 7oL-pr0pionylthiotestosterone propionate as a glass; E =2.4;3;

l r viol xtinction cocfl i nt 16.4% at 38 The r a ion-m x u on ent ate o d y es Example 6 A mixture of 1.1 parts by weight of 17fl-hydroxy-4,6 androstadien-3-one propionate and 1 part by volume of S-methylbutanethiolic acid is heated on the steam bath The reaction mixture is concentrated to dryness in vacuo, the residue dissolved in 100 partsby; v.01- ume of benzene and the resulting solution chromato for 4 hours.

graphed on silica gel. The chromatographic column is washed with 2000 parts by volume of benzene and eluted with 2000 parts by volume of .5 ethyl acetate in benzene.

millirnicrons. This compound exhibits infrared absorption maxima at about 5.75, 5.9; 6.15 and 8.4 microns.

What is claimed is: l. A 7-acylthio-4e androstenone of; the formula.

wherein acyl is a (lowe rlalkanoyl radical and Z isselected from the group consisting; of carbonyl, hydroxymethylene, (lower)alkanoyloxymethylene and benzoyloxymethylene. e

2. 7-acetylthio@4-androstene-3,17-dione. 3. 'l-acetylthiotestosterone benzoate. 4. 7-propionylthiotestosterone. v 5 7 -propionylthiotest osterone propionate.

No references cited.

7 The solvent is removed from the eluate to yield 7a-isovalerylthiotestosterone propionate as a glass having, a maximum in the ultraviolet absorption spectra at 238 V 

1. A 7-ACYLTHIO-4-ANDROSTENONE OF THE FORMULA 